Sweat sensing technologies have enormous potential for applications ranging from athletics, to neonates, to pharmacological monitoring, to personal digital health, to name a few applications. This is because sweat contains many of the same biomarkers, chemicals, or solutes that are carried in blood, which can provide significant information which enables one to diagnose ailments, health status, toxins, performance, and other physiological attributes even in advance of any physical sign. Furthermore sweat itself, and the action of sweating, or other parameters, attributes, solutes, or features on or near skin or beneath the skin, can be measured to further reveal physiological information.
Sweat has significant potential as a sensing paradigm, but it has not emerged beyond decades-old usage in infant chloride assays for Cystic Fibrosis (e.g. Wescor Macroduct system) or in illicit drug monitoring patches (e.g. PharmCheck drugs of abuse patch by PharmChem). The majority of medical literature discloses slow and inconvenient sweat stimulation and collection, transport of the sample to a lab, and then analysis of the sample by a bench-top machine and a trained expert. All of this is so labor intensive, complicated, and costly, that in most cases, one would just as well implement a blood draw since it is the gold standard for most forms of high performance biomarker sensing. Hence, sweat sensing has not achieved its fullest potential for biosensing, especially for continuous or repeated biosensing or monitoring. Furthermore, attempts at using sweat to sense ‘holy grails’ such as glucose have failed to produce viable commercial products, reducing the publically perceived capability and opportunity space for sweat sensing. A similar conclusion has been made very recently in a substantial 2014 review provided by Castro titled “Sweat: A sample with limited present applications and promising future in metabolomics”, which states: “The main limitations of sweat as clinical sample are the difficulty to produce enough sweat for analysis, sample evaporation, lack of appropriate sampling devices, need for a trained staff, and errors in the results owing to the presence of pilocarpine. In dealing with quantitative measurements, the main drawback is normalization of the sampled volume.”
Many of these drawbacks stated above can be resolved by creating novel and advanced interplays of chemicals, materials, sensors, electronics, microfluidics, algorithms, computing, software, systems, and other features or designs, in a manner that affordably, effectively, conveniently, intelligently, or reliably brings sweat sensing technology into intimate proximity with sweat as it is generated. Sweat sensing therefore becomes a compelling new paradigm that clearly was overlooked in terms of its ultimate potential as a biosensing platform.
Sweat sensors have many potential advantages over other biofluid sensors. But one potentially confounding factor is that prolonged stimulation of sweat can be problematic as some individuals can be hyper sensitive to prolonged stimulation of sweat or their glands will adapt to sweat stimulation and provide no or reduced response to sweat stimulation by heat, electricity, iontophoresis, or other means. Furthermore, for prolonged stimulation, risk of electrode detachment is a risk, and can even be a risk at the onset of stimulation. Solutions for solving these risks are lacking.
The number of active sweat glands varies greatly among different people, though comparisons between different areas (ex. axillae versus groin) show the same directional changes (certain areas always have more active sweat glands while others always have fewer). The palm is estimated to have around 370 sweat glands per cm2; the back of the hand 200 per cm2; the forehead 175 per cm2; the breast, abdomen, and forearm 155 per cm2; and the back and legs 60-80 per cm2. Assuming use of a sweat gland density of 100/cm2, a sensor that is 0.55 cm in radius (1.1 cm in diameter) would cover ˜1 cm2 area or approximately 100 sweat glands. According to “Dermatology: an illustrated color text” 5th edition, the human body excretes a minimum of 0.5 liter per day of sweat, and has 2.5 million sweat glands on average and there are 1440 minutes per day. For prepubescent children, these sweat volumes are typically lower. For 2.5 million glands that rate is 0.2 μl per gland per day or 0.14 nl/min/gland. This is the minimum ‘average’ sweat rate generated per pore, on average, with some possible exceptions being where sweating increases slightly on its own (such as measuring sleep cycles, etc.). Again, from “Dermatology: an illustrated color text” 5th edition, the maximum sweat generated per person per day is 10 liters which on average is 4 μL per gland maximum per day, or about 3 nL/min/gland. This is about 20× higher than the minimum rate.
According to Buono 1992, J. Derm. Sci. 4, 33-37, “Cholinergic sensitivity of the eccrine sweat gland in trained and untrained men”, the maximum sweat rates generated by pilocarpine stimulation are about 4 nL/min/gland for untrained men and 8 nL/min/gland for trained (exercising often) men. Other sources indicate maximum sweat rates of an adult can be up to 2-4 liters per hour or 10-14 liters per day (10-15 g/min·m2), which based on the per hour number translates to 20 nL/min/gland or 3 nL/min/gland. Sweat stimulation data from “Pharmacologic responsiveness of isolated single eccrine sweat glands” by K. Sato and F. Sato (the data was for extracted and isolated monkey sweat glands, which are very similar to human ones), suggests a rate up to ˜5 nL/min/gland is possible with stimulation, and several types of sweat stimulating substances are disclosed. For simplicity, we can conclude that the minimum sweat on average is ˜0.1 nL/min/gland and the maximum is ˜5 nL/min/gland, which is about a 50× difference between the two.
Based on the assumption of a sweat gland density of 100/cm2, a sensor that is 0.55 cm in radius (1.1 cm in diameter) would cover ˜1 cm2 area or approximately 100 sweat glands. Assuming a dead volume under each sensor of 50 μm height or 50×10−4 cm, and that same 1 cm2 area, provides a volume of 50E-4 cm3 or about 50E-4 mL or 5 μL of volume. With the maximum rate of 5 nL/min/gland and 100 glands it would require 10 minutes to fully refresh the dead volume. With the minimum rate of 0.1 nL/min/gland and 100 glands it would require 500 minutes or 8 hours to fully refresh the dead volume. If the dead volume could be reduced by 10× to 5 μm roughly, the max and min times would be 1 minute and 1 hour, roughly respectively, but the min rate would be subject to diffusion and other contamination issues (and 5 μm dead volume height could be technically challenging). Consider the fluidic component between a sensor and the skin to be a 25 μm thick piece of paper or glass fiber with, which at 1 cm2 equates to a volume of 2.5 μL of volume and if the paper was 50% porous (50% solids) then the dead volume would be 1.25 μL. With the maximum rate of 5 nL/min/gland and 100 glands it would require 2.5 minutes to fully refresh the dead volume. With the minimum rate of 0.1 nL/min/gland and 100 glands it would require ˜100 minutes or ˜2 hours to fully refresh the dead volume.
Sweat stimulation is commonly known to be achieved by one of several means. Sweat activation has been promoted by simple thermal stimulation, by intradermal injection of drugs such as methylcholine or pilocarpine, and by dermal introduction of such drugs using iontophoresis. Gibson and Cooke's device for iontophoresis, one of the most employed devices, provides DC current and uses large lead electrodes lined with porous material. The positive pole is dampened with 2% pilocarpine hydrochloride, and the negative one with 0.9% NaCl solution. Sweat can also be generated by orally administering a drug. Sweat can also be controlled or created by asking the subject using the patch to enact or increase activities or conditions which cause them to sweat.
Sweat rate can also be measured real time in several ways. Sodium can be utilized to measure sweat rate real time (higher sweat rate, higher concentration), as it is excreted by the sweat gland during sweating. Chloride can be utilized to measure sweat rate (higher sweat rate, higher concentration), as it is excreted by the sweat gland during sweating. Both sodium and chloride can be measured using ion-selective electrodes or sealed reference electrodes, for example placed in the sweat sensor itself and measured real time as sweat emerges onto the skin. Sato 1989, pg. 551 provides details on sweat rate vs. concentration of sodium & chloride. Electrical impedance can also be utilized to measure sweat rate. Grimnes 2011 and Tronstad 2013 demonstrate impedance and sweat rate correlations. Impedance and Na concentration, and or other measurements can be made and used to calculate at least roughly the sweat pore density and sweat flow rate from individual sweat glands, and coupled with sweat sensing or collection area to determine an overall sweat flow rate to a sensor. More indirect measurements of sweat rate are also possible through common electronic/optical/chemical measurements, including those such as pulse, pulse-oxygenation, respiration, heart rate variability, activity level, and 3-axis accelerometry, or other common readings published by Fitbit, Nike Fuel, Zephyr Technology, and others in the current wearables space, or demonstrated previously in the prior art.
With reference to FIG. 1A, a prior art sweat stimulation and sensing device 10 is positioned on skin 12 and is provided with features shown relevant to the present invention. The device 10 is adhered to the skin 12 with an adhesive 14 which carries a substrate 13, control electronics 16, at least one sensor 18, a microfluidic component 20, a reservoir or gel with pilocarpine referred to as pilocarpine source 22, an iontophoresis electrode 24, and counter electrode 26. The electrodes 24 and 26 are electrically conductive with and through the skin 12 by virtue of the conductance of materials 22, 20 and 14 and, in some cases adhesive 14 can be locally removed beneath one or more electrodes or sensors to improve conductance with the skin and/or to improve collection or interface with sweat. Adhesives can be functional as tacky hydrogels as well which promote robust electrical, fluidic, and iontophoretic contact with skin (as commercially available examples such as those by SkinTact for ECG electrodes). With reference to FIG. 1B, a top view of connections to the electronics 16 is shown, such connections by example only and not representing a limiting configuration. The electronics 16 can be a simple as a controlled current source and sensing electronics only, or more complex including computing, communication, a battery, or other features. Again, in some embodiments, the electronics may be much simpler or not needed at all.
With further reference to FIGS. 1A and 1B, if the device 10 were to stimulate sweat by virtue of iontophoretically driving a stimulating drug such as pilocarpine from the source 22 into the skin 12, it could conventionally do so for several minutes and stimulate sweat that could be collected for 10-30 minutes by the microfluidic component 20 and flow over the sensor 18 which could detect one or more solutes of interest in the sweat. This conventional stimulation and collection time frame is typical and similar to that broadly used for infant-chloride assays for cystic fibrosis testing, such as found in products by Wescor Corporation. Sweat sensors have advantages over other biofluid sensors, but one potentially confounding factor is that prolonged stimulation of sweat for more than 30 minutes could be problematic as some individuals can be hyper sensitive to prolonged stimulation of sweat or their glands, or will adapt to sweat stimulation and provide no or reduced response to sweat stimulation by heat, electricity, iontophoresis, or other means. Furthermore, for prolonged stimulation, electrode detachment can be a risk, or even be a risk at the onset of stimulation. Solutions for solving these risks are lacking. Furthermore, the stimulation can interfere with the quality of the sensing, and therefore needs to be resolved as well.